Forum for Science, Industry and Business

Protein 'tubules' free avian flu virus from immune recognition

07.11.2008

A protein found in the virulent avian influenza virus strain called H5N1 forms tiny tubules in which it "hides" the pieces of double-stranded RNA formed during viral infection, which otherwise would prompt an antiviral immune response from infected cells, said Baylor College of Medicine researchers in an online report in the journal Nature.

Two domains or portions of the protein NS1 combine to form tiny tubules where double-stranded RNA is hidden from the immune system, said Dr. B. V. Venkataram Prasad, professor of biochemistry and molecular biology, molecular virology and microbiology at BCM and his student, Dr. Zachary A. Bornholdt (now of the Scripps Research Institute in La Jolla, California).

"Once we confirm the importance of this structural information, we should be able to design drugs to block this action," said Prasad. "There are other things the protein could do to interfere with different immune mechanisms. We don't know if this is the only mechanism or if there are others that also come into play during influenza virus infection."

The two researchers had already recognized the importance of the protein NS1 in the virulence of influenza viruses and particularly, H5N1, a form of avian flu associated with more than half the deaths in a 2004 "bird flu" outbreak that resulted in 50 human cases and 36 deaths in Vietnam, China and Thailand. In all but one case, experts ruled out human-to-human spread of the virus. In a previous report, Prasad and Bornholdt described the structure of an area of the protein called the effector domain. In this report, a series of elegant experiments designed and carried out over eight months by Bornholdt allowed the two scientists to "crystallize" the entire protein.

By doing this, they were able to determine its structure using a technique called X-ray crystallography. This technique enables scientists to determine the three-dimensional structure of proteins and other bio-molecules by scattering X-rays through a crystal of the molecule. They substantiated their structure with cryo-electron microscopy, which makes images of tiny frozen structures using an extremely powerful electron microscope.

That structure revealed a previously unsuspected idiosyncrasy of NS1 in H5N1 that could explain the virus' virulence. In most cases, when an infected cell is exposed to a virus, double-stranded RNA molecules are formed triggering a potent anti-viral response that involves production of interferon.

However, the two domains of NS1 in this H5N1 interact to form tiny tubules. The double-stranded RNA is hidden or sequestered in these structures. The cell never sees a significant length of the RNA and does not marshal its immune forces to the fight the virus. Prasad and Bornholdt believe also that cellular factor binding sites found on the surface of the tubules also play a role in fooling the immune system.

"This is only one structure," said Prasad. "We need to see if this holds up with other NS1 structures from other influenza viruses."

Bornholdt's technique for crystallizing the protein will prove valuable in pursuing this work, said Prasad.

"Is this a common mechanism for eluding the immune system?" he said. He said hopes to build a library to NS1 structures to facilitate future studies designed to fight influenza worldwide.

While H5N1 is not usually transmitted from human-to-human at this point, a small change in its genetic structure – perhaps an exchange of genes with a more easily transmitted flu virus – could change that, he said. Developing drugs to fight the virus could prove life-saving in a pandemic.

Die letzten 5 Focus-News des innovations-reports im Überblick:

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...